No therapeutic options are currently available to treat the life-long neurological disabilities seen in more than 50% of patients surviving after herpes simplex virus (HSV)-1 encephalitis (HSE). It is widely believed that long-term brain damage related to HSE, in large part, is the direct consequence of an exacerbated neuroimmune response, which is sustained even after suppression or clearance of the pathogen. It is also well known that neurogenesis in the adult mammalian brain is accomplished by a small population of self-renewing, undifferentiated cells called neural stem cells (NSCs) that migrate to areas of brain injury and are thought to play a role in cellular replacement as a mechanism of repair. NSC migration into regions of brain injury converges with a variety of trafficking immune cells at the lesion site, suggesting an active interaction between these cells. In the present proposal, it is hypothesized that a dysregulated immune response to HSV-1 brain infection alters neurogenic mechanisms in the central nervous system (CNS) culminating in long-term neurological consequences. Little, if anything is known about the impact of neuroimmune responses on NSCs in the context of viral encephalitis. To fill this major gap in knowledge, we will use a mouse model of HSE which mimics the neuropathological sequelae and neurological deficits observed in patients. The central hypothesis of this proposal is that the interactions between NSCs and activated immune cells during HSV- 1 brain infection alter the fate of neural progenitors culminating in neurological damage manifested by behavioral deficits. We propose two approaches to delineate mechanisms that alter NSC responses and fate in a virus-induced inflammatory milieu. The first approach will address the impact of T lymphocytes in directing NSC function during HSE. In this series of experiments, we will define the role of activated CD8 T-cells in modulating NSC properties, including the ability to proliferate, migrate, and differentiate into neural cell types. In addition, we will investigate the role of T cell interactions with microglia as a potential mechanism for altering NSC functions. Secondly, we will determine if NSCs promote a tissue healing microenvironment by inhibiting T-cell activation. The functional implications of these bidirectional responses will be assessed by determining if NSCs restore the neurological deficits following HSE using behavioral outcome measures for spatial memory performance. The proposed research project will develop a new understanding of interactions between NSCs and the immune milieu generated by activated microglia, T-cells, and their mediators during viral encephalitis. Insights gained from this research project are hoped to lead to new therapeutic and preventative approaches to long-term brain damage caused by viral encephalitis.